Age is associated with changes in the brain environment which predispose towards neurodegenerative disease. One contributing element to the brain environment is the brain's resident monocytic cells, the microglia. Activation of microglia can result in release of inflammatory factors. The general perception was that more microglial activation would cause greater release of inflammatory mediators, which would contribute to more neurodegeneration in Alzheimer's disease, Parkinsons's disease and stroke. However, studies in several laboratories now indicate that some forms of microglial activation can benefit neurodegenerative disease. Studies of peripheral macrophages have led to identification of several distinct activation states, referred to variously as M1 and M2 or classical and alternative. These are characterized by different markers being expressed and different functions of the cells. To date, distinct activation states of microglia in brain have not been well characterized. In aim 1 we will test the ability of M1 specific and M2 specific microglial activation cocktails to induce expression of multiple markers, some general and some specific to each activation state. It is anticipated that the magnitude and duration of responses to these agents will be altered with aging, with old mice having a greater propensity towards an M1 proinflammatory activation state. A second aim will investigate whether changes in the brain environment regulate the amount of histopathology present. For example, in APP transgenic mouse models of amyloid deposition/the amount of Abeta deposited in brain increases with age. But, it is knot known whether this occurs because of the passage of time, or whether the age of mouse is playing a critical role in the amount of Abeta deposited. We will examine this by suppressing Abeta deposition for 6 mo in two different mouse models and then releasing it from suppression. If the Abeta deposition accumulates at a similar but delayed rate, time will be viewed as the critical factor. However, if the Abeta deposition reaches the same level in both conditions several months after the release from suppression, then clearly the aged brain environment is playing a critical role. Finally, in collaboration with other projects in the program, we will investigate whether increases in microglial activation caused by depletion of noradrenaline, or decreases in microglial activation associated with LFA-1 null condition modify the extent of amyloid deposition and memory loss in APP transgenic mice.